This invention relates to a method of treating depression in a patient by oral or non-oral administration of 2S,2xe2x80x2S-methyl 2-phenyl-2-(2xe2x80x2-piperidyl) acetate, commonly known as 1-threo-methylphenidate, hereinafter referred to as 1-MPH and to pharmaceutical compositions containing 1-MPH designed to deliver 1-MPH to the central nervous system. More particularly the method of treatment is designed to provide relief to a depressed patient who is awaiting the onset of the antidepressive action of an antidepressant such as a selective serotonin re-uptake inhibitor, or any other class of antidepressant that requires administration over 2 to 6 weeks to demonstrate therapeutic effect.
Orally administered racemic d1-threo-methylphenidate (d1-MPH) is widely used in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in children and adults and also in the treatment of depression in patients suffering from cancer or AIDS, compulsive shopping disorder, narcolepsy, and hypersomnia. It is known that the therapeutic effect of d1-MPH in the treatment of ADHD in children is attributable to d-MPH (Srinivas et al, Clin. Pharmacol. Therap. 52, 561 to 568, 1992). Until recently, however, little was known about the potential pharmacological and/or therapeutic roles of 1-MPH because concentrations of 1-MPH in plasma and brain are very low due to extensive enantioselective first pass metabolism of 1-MPH after oral administration of d1-MPH (Srinivas et al, Pharm. Res. 10, 14 to 21, 1993). After intravenous administration of d1-MPH, however, both enantiomers of threo-methylphenidate are taken up into the brain although their patterns of distribution are different (Ding et al, Psychopharmacology 131, 71 to 78, 1997).
The use of oral stimulants such as dextroamphetamine or d1-MPH in the treatment of severe depressive disorders in the elderly or terminally ill depressed patients has been the subject of many studies over the years. After reviewing 85 publications on the subject, Satel and Nelson (J. Clin. Psychiat. 50, 241 to 249, 1989) were critical of the fact that many of the studies reported were methodologically unsophisticated and/or uncontrolled. They concluded that while stimulants are no more effective than a placebo in the treatment of primary depression, stimulants may be of value in the treatment of refractory patients and medically ill patients. Similarly, Chiarello and Cole (Arch. Gen. Psychiat. 44, 276 to 285, 1997) reviewed 81 publications and concluded that many of the older studies are inadequate although there was some evidence to support the use of psychostimulants in selected clinical instances. Emptage and Smith (Annals of Pharmacotherapy, 30, 151 to 157, 1996) reviewed 43 studies published from 1986 to 1995 and concluded that oralxe2x80x94MPH appears to be a safe and effective treatment for depressed, medically ill, elderly patients to provoke a rapid onset of antidepressant activity. Recently Wallace and co-workers (Am. J. Psychiat. 152, 929 to 931, 1995) conducted what they termed the first placebo-controlled double blind trial to demonstrate the efficacy of oral d1-MPH in older, medically ill depressed patients. The benefit of oral d1-MPH was statistically and clinically significant despite the small number of patients in the study (n=16). Depressive symptoms decreased markedly in 7 subjects (Hamilton depression scale decreased by  greater than 55%), moderately in a further 3 subjects (Hamilton depression scale decreased by 30 to 55%), minimally in 3 subjects (Hamilton depression scale decreased by  less than 30%) and three patients were dropped from the study.
It is an objective of the invention to provide a method of treating a depressed patient to provide immediate relief from intense dysphoria by administering to the patient via an oral or non-oral route, a therapeutically effective amount of 1-MPH which refers herein to the base or hydrochloride salt or any other pharmaceutically acceptable salts thereof.
A further objective of the invention is to provide a method of treating a depressed mammal and particularly a depressed human patient with repeated doses of 1-MPH, either in immediate release form or sustained release form to provide relief while the patient awaits the onset of action of a conventional antidepressant drug.
A further objective of the invention to provide a test to ascertain how responsive a patient may be to certain forms of antidepressant therapy by administering 1-MPH orally or non-orally to the patient, observing the patient""s response to the 1-MHP and utilizing that information to predict how effectively such a patient would be expected to respond to treatment with conventional anti-depressants which take 2 to 6 weeks to become optimally effective.
According to this invention, 1-MPH and/or its salts is a valuable rapidly acting anti-depressant and/or anti-dysphoric when administered by a route that avoids first pass metabolism or given orally in large enough doses to saturate and overwhelm the first pass metabolism. It may be used according to the present invention to treat a patient suffering from depression by systemically administering to the patient, in an oral or non-oral form, a clinically effective dose of 1-MPH. The 1-MPH may either be in the form of its free base or in the form of a pharmaceutically acceptable salt, such as the hydrochloride salt, the acetate salt, the maleate salt or any other pharmaceutically acceptable acid addition salt.
The oral routes of administration that avoid the first pass metabolism are preferably parenteral, sub-lingual or intra-nasal administration or via the buccal mucosae.
The 1-MPH used according to the present invention has an enantiomeric purity of at least 95% and therefore contains no more than 5% d-MPH; the latter enantiomer may potentially be abused. Preferably the 1-MPH is enantiomerically pure.
The 1-MPH may be used to provide rapid antidepressant action for the relief of severe depression in, for example terminal cancer patients, patients with AIDS depression, or in severely depressed patients with suicidal ideation. The 1-MPH may also be useful as a diagnostic tool to identify severely depressed patients who are responders to serotonin re-uptake inhibitors (SSRIs). Examples of these SSRIs include fluoxetine hydrochloride, venlafaxine hydrochloride, paroxetine hydrochloride, nefazodone hydrochloride, and sertraline hydrochloride.
The drug is particularly useful in the treatment of severely depressed hospitalized patients and in depressed suicidal patients to provide immediate relief from their intense dysphoria. The drug may be given repeatedly, either as an immediate release or as a sustained release formulation to provide relief while the patient awaits the onset of conventional antidepressants which typically take 3 to 6 weeks to become effective. These conventional antidepressants can include serotonin re-uptake inhibitors (SSRIs) which have been discussed hereinabove as well as any other pharmaceutical composition that is recognized as safe and effective in the treatment of depression. Such other pharmaceutical compositions include atypical antidepressants which are antidepressant compounds with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors. Examples of such compounds are nefazodone and bupropion. Such other pharmaceutical compositions also include tricyclic antidepressants such as amitriptyline, imipramine, doxepin, maprotiline, protriptyline, nortriptyline, desimipramine, clomipramine, trimipramine or any other conventional tricyclic antidepressant.
The 1-MPH may be used to help severely depressed patients to recover a sufficiently euthymic mood to restore in them feelings of hope and a renewed will to live.
Another feature of the present invention is a diagnostic test which includes the 1-MPH in a method to determine how responsive a patient may be to certain forms of anti-depressant therapy. Patients who respond dramatically to an adequate dose of 1-MPH are patients with diminished serotonin transmission and a strongly lateralized serotonin system. Positive response to 1-MPH would indicate treatment with a drug such as a selective serotonin re-uptake inhibitor (SSRI) that would enhance serotonin transmission. While SSRIs are effective in many patients, some 30% of depression patients do not respond and less than half respond completely. Thus a positive response to 1-MPH is a valuable indicator that the patient is an SSRI responder and that it is worth persisting with an SSRI during the weeks that it takes for this class of drugs to be effective in treating depression.
The 1-MPH may be administered systemically by one or more oral or non-oral routes of administration. Routes of administration include rectal administration in the form of liquids or suppositories, as well as a number of alternative routes of administration, including absorption through the nasal mucosae or the buccal mucosae, or the sub-lingual mucosae, various means of percutaneous administration by, for example, use of a transdermal patch, or by subcutaneous, intravenous, intramuscular, or intraperitoneal injection.
The daily dosage of the 1-MPH administered to a patient suffering from depression is 5 to 500 mg, preferably 25 to 250 mg/day and more preferably 25 to 125 mg/day.
The 1-MPH may be orally administered in a per unit dose of 5 to 1000 mg. The oral dose form may be made into formulations such as tablets, lozenges, capsules, powders, aqueous or non-aqueous oral suspensions, syrups, elixirs or aqueous solutions.
The 1-MPH can be isolated from the racemic mixture of d1-MPH by preparative chiral high performance liquid chromatography (HPLC). In this procedure a non-polar octadecasilane HPLC column (25.4 mmxc3x97250 mm) is used in combination with a mobile phase (dichloromethane/acetonitrile) containing a chiral discriminator, namely xcex1-10-camphorsulfonic acid, and a competing base, namely triethylamine. See Lim et al, 1985.
The application of medicinal substances to the skin is an effective route of delivery of many drugs to the systemic circulation. The skin often has been referred to as the largest of the body organs; an average adult""s skin has a surface area of about 2 m2. Its accessibility and the opportunity it affords to maintain applied preparations intact for a prolonged time have resulted in its increasing use as a route of drug administration, whether for local, regional or systemic effects. Drugs are applied to the skin to elicit one or more of four general effects: an effect on the skin surface, an effect within the stratum corneum, a more deep-seated effect requiring penetration into the epidermis and dermis or a systemic effect resulting from delivery of sufficient drug through the epidermis and the dermis to the vasculature to produce therapeutic system concentrations.
Generally the drug is suspended/dispersed in a vehicle such as propylene glycol/isopropyl myristate. Other additives used are p-aminobenzoic acid or benzyl peroxide. The drug release from its vehicle is a function of concentration, solubility in the vehicle and the partition coefficient between the vehicle and the receptor site. Percutaneous absorption of the drug is enhanced by the use of occlusive techniques or by the use of penetration enhancers. Penetration Enhancers such as polyols e.g. glycerin, have a direct effect on the permeability of the skin. They act by increasing the thermodynamic activity of the penetrant, thereby increasing the effective escaping tendency and concentration gradient of the diffusing drug.
Generally the formulation for the patch is composed of two/three layers. Proceeding from the outer surface to the film in contact with the skin, these layers are a soft flexible backing of translucent polyethylene film, a drug containing film composed of acrylate adhesive matrix or ethylene-vinyl acetate and a protective liner composed of polyester film.
For 1-MPH, solvents such as various alcohols, dimethyl sulfoxide or decylmethyl sulfoxide may be utilized, and anionic surfactants such as sodium lauryl sulfate or various cationic, amphoteric or non-ionic surfactants may be appropriate.
Sublingual tablets are designed to dissolve very rapidly. Examples of such formulations include ergotamine tartrate, isosorbide dinitrate, isoproterenol HCl. The formulation of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but occasionally dextrose and mannitol. The process of making sublingual tablets involves moistening the blended powder components with an alcoho1-water solvent system containing approximately 60% alcohol and 40% water.
In addition to 1-MPH, the prototype formulation for sublingual tablets may contain a binder such as povidone or HPMC, diluents such as lactose, mannitol, starch or cellulose, a disintegrant such as pregelatinized or modified starch, lubricants such as magnesium stearate, stearic acid or hydrogenated vegetable oil, a sweetener such as saccharin or sucrose and suitable flavoring and coloring agents.
For many years, the nasal delivery was used primarily for local action on the nasal mucosae. Despite its use in systemic delivery of desmopressin and vasopressin, its use as an alternate route for poorly absorbed oral drugs seems to have been ignored until recently. By virtue of relatively rapid drug absorption, possible bypassing of presystemic clearance, and relative ease of administration, delivery of drugs by nasal route offers an attractive alternative for administering systemically active drugs.
The prototype formulation for nasal solutions will contain 1-MPH dissolved in a suitable aqueous or non-aqueous solvent such as propylene glycol, an antioxidant such as ascorbic acid and aromatic oils as flavoring agents. The formulation may also contain suitable propellant(s).
The use of suppositories dates back to writings of the early Egyptians, Greeks and Romans. However it is only recently efforts are being carried out to correlate in vitro results with in vivo studies. The rectal suppositories for adults are usually tapered at one or both ends and weigh about 2 g each. The return is about 150 mm in length and contains a small amount of fluid of low buffering capacity with a pH of about 7.2. The suppository base such as cocoa butter is immiscible with aqueous tissue fluids but melts at body temperature.
In the prototype formulation for suppositories, the drug (1-MPH) is typically dissolved in a base such as cocoa butter, polyethylene glycol or glycerinated gelatin. The suppository mixture is poured and cooled in individual molds formed from plastic or foil and the excess is trimmed off and units are sealed and cut into desired packaging. The suppositories with low-melting ingredients are best stored in a cool place. Cocoa oil suppositories should be refrigerated.
For intravenous or subcutaneous injection, a suitable 1-MPH acid salt will be supplied as sterile powder or crystals in sealed ampoules or vials. The formulation may be reconstituted in a sterile intravenous preparation such as normal saline, dextrose or water for injection. Alternatively, the intravenous formulation may be supplied as sterile aqueous solution of a suitable acid salt of 1-MPH in a sterile intravenous preparation such as normal saline, dextrose or water for injection.
For intramuscular administration, an acid salt of 1-MPH may be formulated as a sterile aqueous solution as described above, or alternatively, 1-MPH base may be dissolved in a suitable oil such as cotton seed oil or sesame oil.